Pain 101—Nerve Damage and Pain from Cancer Treatment: Prevention Is Better Than Cure

Editor’s Note: Seven early-career pain researchers took part in the IASP Pain Research Forum Correspondents programduring the 7th International Congress on Neuropathic Pain (NeuPSIG 2019), which took place May 9-11, 2019, in London, UK. This unique science communications training program provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers and to patients and the broader public. Here, PRF Correspondent Nadia Soliman, a PhD candidate at Imperial College London, UK, summarizes a plenary talk from the Congress delivered by Lesley Colvin, MBChB, PhD, an expert on the nerve damage and subsequent pain that cancer treatment can cause.

There is a growing population of cancer survivors who are now suffering from chemotherapy-induced peripheral neuropathy (CIPN) and often there is little to help them.

It was with this stark reality that Lesley Colvin began her plenary talk at the 7th International Congress on Neuropathic Pain, a meeting of the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG). Colvin is Chair of Pain Medicine in the Division of Population Health and Genomics at the University of Dundee, Scotland, UK.

CIPN is a condition in which chemotherapy—the treatment for the cancer—causes damage to nerves, leading to severe pain that can last for many years. In fact, many patients that Colvin sees have pain so intense that they wish they had not survived the cancer; their quality of life had been diminished to a standard considered worse than death.

The problem of CIPN has been getting worse as cancer treatment improves and people survive longer. But there is reason for optimism. The take-home message of Colvin’s talk was that the focus should be on improving the assessment and diagnosis of CIPN and on identifying new ways to prevent those at greatest risk from developing the condition in the first place.

A growing problem
CIPN is a disabling pain condition that is becoming more and more common. This is because there are increased numbers of people with cancer, coupled with improved treatment of cancer, which means that many more individuals with cancer are surviving longer than they did in the past.

Many commonly used chemotherapy drugs can cause damage to peripheral nerves. This includes oxaliplatin, cisplatin and paclitaxel, which are broadly used to treat different cancers and are associated with increased risk of CIPN.

However, not all chemotherapies will lead to CIPN. Exactly how these drugs damage nerves is complex and not fully understood. Changes in the activity of proteins that set the electrical excitability of nerve cells, inflammation, and abnormal workings of mitochondria, the energy “powerhouses” of the cell, are just a few of the processes at play.

CIPN can occur very quickly during chemotherapy—even within five days of beginning the drug. If CIPN is severe, that may require a decrease in the amount of chemotherapy, or a patient may choose to stop before completing a planned course of chemotherapy. This will have an impact on how effective the chemotherapy is and may affect survival.

In many cases, CIPN will resolve after chemotherapy treatment is complete. But for some people, it can persist for months or even years. The prevalence of CIPN one month after finishing chemotherapy is 68%, 60% at 3 months, and 30% at six months or more.

Unfortunately, current treatments for CIPN often don’t work, and they can produce unwanted side effects. A better understanding of what is happening in the nervous system during CIPN will be essential for the development of new and improved treatment options.

What kind of pain?
When it comes to the pain of CIPN, it’s a complicated picture. CIPN can feature both loss and gain of sensation. Some people experience mechanical allodynia, a phenomenon where something that doesn’t usually cause pain now causes excruciating pain. For example, CIPN patients may describe wearing clothes on their skin as extremely painful.

Thermal allodynia—sensitivity to temperature, and particularly to cold temperature—is another type of pain that CIPN patients experience. Patients also report hyperalgesia, which is increased sensitivity to painful stimuli, as well as dysesthesia, which is abnormal, unpleasant sensation such as painful burning, tingling, or itching, among others.

Patients with CIPN may describe their pain as burning, shooting, stabbing, electric shocks, “like walking on glass” and “as if wearing gloves with bees inside.”

The symptoms of CIPN originate in the hands and feet, which is why CIPN is described as a “glove and stocking” neuropathy. Also, while CIPN predominantly affects sensation, it can also affect the autonomic nervous system (which controls functions outside of conscious awareness), fine motor function as well as proprioception, which is the body’s sense of its position in space and of movement.

Who is at risk of developing CIPN?
It’s important to be able to identify who is most at risk of developing CIPN. So far, researchers have identified several factors that are associated with an increased risk of developing the condition. These risk factors include older age, taking other medications such as cardiovascular drugs, prolonged use of opioids, as well as the presence of other health conditions such as diabetes or HIV infection. Excess alcohol consumption, smoking and obesity also increase the risk of CIPN.

Some of these risk factors can be modified before starting chemotherapy. But it may be difficult to make lifestyle changes such as reducing smoking or alcohol intake during what is already a very stressful time for patients.

In addition, evidence from studies in patients and in animal models of CIPN suggest there may be genetic factors that increase the risk. This includes genes that regulate how the body metabolizes drugs, how well the mitochondria function, and the formation and growth of nerve cells, all of which may be linked to the underlying neurobiological causes of CIPN. The type and dose of chemotherapy also matters.

Genetics are now part of the consideration of what chemotherapy and other cancer treatments will be most appropriate for patients. But the understanding of the risk of toxicity from these therapies is still poor. To determine the best treatment approach and possibly tailor treatment to each person, a better understanding of a patient’s genetic makeup and disease phenotype (the observable characteristics of a disease) is necessary. It’s also important to link the signs and symptoms of CIPN to the toxicity of treatments and the underlying neurobiological processes that drive CIPN.

Looking at the brain
During her talk, Colvin described a recent study that used brain imaging to learn if it is possible to identify patients who may be at risk of developing CIPN. This is of interest since both animal and human studies of other neuropathic pain conditions have shown an important role for the brain during those conditions. There is also evidence to suggest that abnormal activity in specific areas of the brain could be used to identify individuals who are vulnerable to developing chronic pain.

The study enrolled thirty patients diagnosed with cancer who had yet to receive chemotherapy. Each of the study participants received brain scans to assess the structure and function of the brain.

The study showed that those who developed acute (short-lasting) CIPN had structural differences in the nucleus accumbens, compared to patients who did not develop CIPN; the nucleus accumbens is a brain structure that plays an important role in the placebo response and in the reward system, and previous studies have shown that changes in the nucleus accumbens increased the vulnerability to develop chronic pain. In particular, this area of the brain was smaller in the patients who developed CIPN. The results suggest that perhaps having more active placebo and reward systems help to prevent CIPN.

The brains of those who developed CIPN also showed differences in function. Here, before developing CIPN, patients showed increased activation in areas of the brain known to regulate pain.

Although there is a need for further confirmation, these early findings show that techniques such as brain imaging have potential to serve as useful clinical biomarkers—observable, measurable indicators of disease in patients—and as a way to identify who is at risk of developing CIPN. This may allow an oncologist to modify the chemotherapy dose before complications occur, which would be a step towards individualized treatment, and could help patients make a more informed choice about whether they want to undergo chemotherapy.

Assessment and prevention: two key challenges
Colvin highlighted two important obstacles to dealing with the growing problem of CIPN.

First, there is a large need to improve the way that CIPN is assessed and diagnosed. Right now there are a number of different approaches to this task, and the lack of consistency makes it difficult to understand the risk factors for CIPN and how CIPN will progress over time. The goal is to create international consensus on how to assess patients and make the diagnosis. This must include consideration of the disease process of neuropathic pain, the coexisting cancer, as well as the toxic insult of chemotherapy.

Colvin suggested that existing guidelines developed by NeuPSIG for assessing neuropathic pain could be applied in the setting of CIPN. However, a more tailored approach may be better since the underlying disease mechanisms of CIPN may be specific to the chemotherapy drug that patients receive. Another important consideration is that completing chemotherapy treatment increases the chances of survival, and so any change in the dose could impact that.

Ultimately, any tool to aid assessment and diagnosis needs to be simple and easy to use for non-specialists. This will allow for the early identification of CIPN so that the condition can be managed better, which may include altering the chemotherapy regimen.

The second challenge Colvin highlighted was in regard to prevention. There are currently no preventive therapies for CIPN. This is a particularly important unmet medical need because current treatment options once CIPN has already developed are limited.

Colvin highlighted two different approaches to prevention. Primary prevention aims to deliver an intervention prior to chemotherapy, to stop the toxic effects of chemotherapy from occurring in the first place. This could be an approach for patients who are at risk of developing CIPN. Secondary prevention would focus on diagnosing CIPN as early as possible so that doctors could then intervene and treat it.

There have been several clinical trials of preventive treatments for CIPN, but they have yet to yield sufficient evidence to recommend any particular preventive therapy. Those studies have looked at, for example, acetyl-L-carnitine, an amino acid that was actually associated with worse outcomes, vitamin E (an antioxidant) as well as omega-3 fatty acids.

But, there is emerging evidence to suggest that melatonin together with vitamin E can prevent CIPN caused by the drug paclitaxel, at least in animal models of the condition. One hypothesis is that melatonin and vitamin E may reduce the damage that occurs in mitochondria in response to chemotherapy.

Colvin ended her talk by highlighting the importance of collaboration: basic scientists, who work on the fundamental workings of CIPN, doctors and patients themselves all need to work together to overcome the challenges this condition presents in terms of effective prevention and treatment.

Ultimately, with a growing population of patients suffering debilitating pain from the nerve damage that chemotherapy can cause, it is crucial to have a better understanding of what happens in the nervous system during CIPN. This knowledge will lead to improved assessment and diagnosis and better ways to identify those who are at risk of developing CIPN, as well as make possible new prevention and treatment strategies.

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